Highly stereoselective Grignard addition to cis-substituted C-cyclopropylaldonitrones. The bisected s-trans transition state can be stabilized effectively by the Lewis acid-coordination

Article abstract of DOI:10.1021/jo048637e

We previously found that Grignard addition to a C-cyclopropylaldonitrone, C-[cis-2-(N,N-diethyl-carbamoyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (1), stereoselectively gave the anti-product 3, in which the stereoselectivity was particularly high

Full text of DOI:10.1021/jo048637e

Highly Stereoselective Grignard Addition to Cis-Substituted
C-Cyclopropylaldonitrones. The Bisected s-Trans Transition State
Can Be Stabilized Effectively by the Lewis Acid-Coordination
Yuji Kazuta, Hiroshi Abe, Akira Matsuda, and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6,
Kita-ku, Sapporo 060-0812, Japan
shu@pharm.hokudai.ac.jp
Received August 5, 2004
We previously found that Grignard addition to a C-cyclopropylaldonitrone, C-[cis-2-(N,N-diethyl-
carbamoyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (1), stereoselectively gave the anti-
product 3, in which the stereoselectivity was particularly high when MgBr2 was the additive. In
this study, the reaction pathway was investigated in detail. The stereoselective addition was initially
thought to occur via either a 1,5-chelation-controlled or a bisected s-trans conformation-controlled
pathway. However, Grignard addition to a nonchelating silyl ether-type substrate, C-[cis-2-(tert-
butyldiphenylsilyloxymethyl)-trans-2-phenylcyclopropyl]-N-benzylaldonitrone (7), also gave the anti-
product 9 with high stereoselectivity suggesting that chelation is not important in the reaction.
Theoretical calculations of C-cyclopropylaldonitrones showed that the coordination of Mg2+ at the
nitrone oxygen significantly stabilizes the bisected s-trans conformer due to the effective hyper-
conjugation between the π* of the nitrone CdN bond and the electron-donating cyclopropane orbitals.
This kind of orbital interaction is able to stabilize the transition state of the nucleophilic addition
and is maximized in the bisected conformation, in which the orbitals of the forming bond and the
cyclopropane C-C bond are in an almost planar arrangement. Thus, the high stereoselectivity can
be explained by nucleophilic attack on the less hindered side of the CdN bond of the substrates in
the Mg2+-coordinated bisected s-trans conformation.
Introduction
the hyperconjugation between the unsaturated bond
orbital and the strong electron-donating orbitals of the
cyclopropane ring.1,7 Nucleophilic additions, such as
hydride reductions, to cyclopropyl ketones often occur
highly stereoselectively probably via the stable bisected
conformation-controlled pathway.8,9 In this paper, we
demonstrate that Lewis acid coordination to C-cyclopro-
pylaldonitrones effectively stabilizes the bisected s-trans
conformation to realize highly stereoselective Grignard
additions.
Cyclopropanes are important in synthetic and medici-
nal chemical studies, and therefore, considerable effort
has been devoted to developing efficient methods for
preparing cyclopropane-related compounds.1-6 Cyclopro-
panes attached to an unsaturated bond, such as vinyl-
cyclopropanes, cyclopropyl ketones, or cyclopropanecar-
baldehydes, preferentially exist in the bisected s-trans
and s-cis conformations, as shown in Figure 1a, due to
In recent years, increasing attention has been focused
on the stereoselective reactions of nitrones with carbon
nucleophilic reagents, which are used in the preparation
of a variety of asymmetric amines.10 We speculated that
C-cyclopropylaldonitrones should also prefer the bisected
conformations, as shown in Figure 1b, which could be
stabilized by the characteristic electron-donating effect
* To whom correspondence should be addressed. Phone: +81-11-
706-3228. Fax: +81-11-706-4980.
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Hudlicky, T. Chem. Rev. 1989, 89, 165-198. (c) Stammer, C. H.
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Med. Chem. 2003, 46, 1980-1988 and references therein.
10.1021/jo048637e CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/17/2004
J. Org. Chem. 2004, 69, 9143-9150
9143

Kazuta et al.
SCHEME 1
FIGURE 1. Bisected s-cis and s-trans conformations of R,â-
unsaturated cyclopropanes.
of the cyclopropane ring, as in vinylcyclopropanes, cyclo-
propyl ketones, and cyclopropanecarbaldehydes.11 The
s-trans conformer seems to be more stable than the s-cis,
TABLE 1. Addition Reactions of Grignard Reagents to
C-Cyclopropylaldonitrone 1a
reagent
(equiv)
additive
(equiv)
yield
(2 + 3)
entry
syn/antib
(6) (a) Ono, S.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 1996, 37,
221-224. (b) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Matsuda, A.
Tetrahedron Lett. 1996, 37, 641-644. (c) Shuto, S.; Ono, S.; Hase, Y.;
Kamiyama, N.; Takada, H.; Yamashita, K.; Matsuda, A. J. Org. Chem.
1996, 61, 915-923. (d) Shuto, S.; Ono, S.; Hase, Y.; Ueno, Y.; Noguchi,
T.; Yoshii, K.; Matsuda, A. J. Med. Chem. 1996, 39, 4844-4852. (e)
Shuto, S.; Ono, S.; Imoto, H.; Yoshii, K.; Matsuda, A. J. Med. Chem.
1998, 41, 3507-3514. (f) Noguchi, T.; Ishii, K.; Imoto, H.; Otubo, Y.;
Shuto, S.; Ono, S.; Matsuda, A.; Yoshii, K. Synapse 1999, 31, 87-96.
(g) Uchino, S.; Watanabe, W.; Nakamura, T.; Shuto, S.; Kazuta, Y.;
Matsuda, A.; Nakajima-Iijima, S.; Kohsaka, S.; Kudo, Y.; Mishina, M.
FEBS Lett. 2001, 69, 2007-2015. (h) Kazuta, Y.; Tsujita, R.; Ogawa,
K.; Hokonohara, T.; Yamashita, K.; Morino, K.; Matsuda, A.; Shuto,
S. Bioorg. Med. Chem. 2002, 10, 1777-1791. (i) Kazuta, Y.; Tsujita,
R.; Uchino, S.; Kamiyama, N.; Mochizuki, D.; Yamashita, K.; Ohmori,
Y.; Yamashita, A.: Yamamoto, T.; Uchino, S.; Kohsaka, S.; Matsuda,
A.; Shuto, S. J. Chem. Soc., Perkin Trans. 1 2002, 1199-1212. (j) Ono,
S.; Ogawa, K.; Yamashita, K.; Yamamoto, T.; Kazuta, Y.; Matsuda,
A.; Shuto, S. Chem. Pharm. Bull. 2002, 50, 966-968. (k) Kazuta, Y.;
Tsujita, R.; Yamashita, K.; Uchino, S.; Kohsaka, S.; Matsuda, A.; Shuto,
S. Bioorg. Med. Chem. 2002, 10, 3829-3848.
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1964, 5, 705-708. (b) Bartell, L. S.; Guillory, J. P. J. Chem. Phys. 1965,
43, 647-654. (c) Volltrauer, H. N.; Schwendemann, R. H. J. Chem.
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Tocanne, J. F. Tetrahedron 1971, 27, 3271-3284. (e) Tocanne, J. F.
Tetrahedron 1972, 28, 389-416. (f) Aroney, M. J.; Calderbank, K. E.;
Stootman, H. J. J. Chem. Soc., Perkin Trans. 2 1973, 1365-1368. (g)
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Org. Chem. 1998, 63, 2850-2853 and references therein.
1
2
3
4
5
6
7
MeMgBr (3)
MeMgBr (3)
MeMgBr (3)
MeMgBr (3)
MeMgBr (3)
EtMgBr (3)
i-PrMgCl (5)
63
32
88
62
81
80
77
10:90
HMPA (5)
TMSCl (2)
ZnBr2 (2)
MgBr2 (2)
MgBr2 (2)
MgBr2 (2)
17:83
14:86
13:87
2:98
only anti
only anti
a The reaction was performed in Et2O/THF (2:1) at -78 °C for
8 h. b Determined by 1H NMR.
due to the steric repulsion between the nitrone moiety
and the cyclopropane ring in the s-cis conformer. Based
on these considerations, we investigated the conformation
and Grignard reaction of a C-cyclopropylaldonitrone,
C-[cis-2-(N,N-diethylcarbamoyl)-trans-2-phenylcyclopro-
pyl]-N-benzylaldonitrone (1) (Scheme 1).11 The X-ray
crystallographic and NOE analyses of 1 showed that it
was stable in the bisected s-trans conformation both in
solid state and in solution. Grignard addition to the
nitrone 1 occurred stereoselectively to give the anti-
product 3, where the stereoselectivity was particularly
high when MgBr2 was used as the additive, as sum-
marized in Table 1.11b The stereochemical results could
be explained by the attack of the nucleophile from the
less-hindered face on the bisected s-trans-conformer A
(Scheme 1).11
We also found that the Grignard additions to the
cyclopropanecarbaldehyde 4 proceeded highly stereo-
selectively to form the anti-product 5 (Scheme 2).6a,c
Moreover, the stereochemical outcome could be under-
stood by attack of the nucleophile on the less hindered
face of the stereoelectronically stabilized bisected s-trans
conformer B of the substrate. Like the nitrone 1, the
aldehyde 4 was shown to be in the bisected s-trans
conformation in the solid state by X-ray crystallographic
analysis.6c However, recent experimental studies and
calculations using 4 and the related substrates 6a-c
have shown that the stereoselective nucleophilic addition
does not occur via the bisected s-trans conformation-
controlled pathway (B) but rather via an unusual seven-
membered 1,4-chelation-controlled pathway (C).12
(8) (a) Descotes, G.; Menet, A.; Collonges, F. Tetrahedron 1973, 29,
2931-2935. (b) Meyers, A. I.; Romine, J. L.; Fleming, S. A. J. Am.
Chem. Soc. 1988, 110, 7245-7247. (c) Lautens, M.; Delanghe, P. H.
M. J. Org. Chem. 1995, 60, 2474-2487. (d) Yokomatsu, T.; Yamagishi,
T.; Suemune, K.; Abe, H.; Kihara, T.; Soeda, S.; Shimeno, H.; Shibuya,
S. Tetrahedron 2000, 56, 7099-7108.
(9) A reaction model predicting the stereochemical outcome of the
cis- and trans-cyclopropyl ketones: Kazuta, Y.; Abe, H.; Yamamoto,
T.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 3511-3521.
(10) For examples, see: (a) Ukaji, Y.; Hatanaka, T.; Ahmed, A.;
Inomata, K. Chem. Lett. 1993, 1313-1316. (b) Dondoni, A.; Franco,
S.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T.; Bertolasi, V.
Chem. Eur. J. 1995, 1, 505. (c) Merino, P.; Castillo, E.; Merchan, F.
L.; Tejero, T. Tetrahedron: Asymmetry 1997, 8, 1725-1729. (d)
Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, F. J. Org. Chem. 1997, 62, 5497-5507. (e) Merino, P.; Castillo,
E.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org. Chem. 1998, 63, 2371-
2374. (f) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron 1998, 54, 12301-12322. (g) Dondoni, A.; Perrone, D.
Aldrichim. Acta 1997, 30, 35-46. (h) Dondoni, A. Synthesis 1998,
1681-1706. (i) Lombardo, M.; Trombini, C. Synthesis 2000, 759-774.
(11) (a) Kazuta, Y.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 2000,
41, 5373-5377. (b) Kazuta, Y.; Shuto, S.; Abe, H.; Matsuda, A. J. Chem.
Soc., Perkin Trans. 1 2001, 599-604. (c) Kazuta, Y.; Shuto, S.; Abe,
H.; Matsuda, A. Org. Biomol. Chem. 2003, 1, 1634.
9144 J. Org. Chem., Vol. 69, No. 26, 2004

Bisected s-Trans Conformation-Controlled Grignard Addition
SCHEME 2
FIGURE 2. Model C-cyclopropylaldonitrones for ab initio
calculations.
basis of DFT (density functional theory) using the Gauss-
ian 98 program.14 The dihedral angle was rotated from
0° to 360° at intervals of 20°, and each conformation was
optimized at RHF/3-21G(d). The single point energies of
the optimized conformers were calculated at RB3LYP/6-
31G(d), and the obtained energy profiles are shown in
Figure 3. For the C-cyclopropylaldonitrone i, the mini-
mum energy values were observed at an angle of 0° (360°)
and 180° (Figure 3a), where it assumes the bisected
s-trans and s-cis conformations, respectively, and the two
conformers have almost the same stability. It is interest-
ing that the energy was not at a maximum in the
perpendicular conformers at 90° (Figure 4a) and 270°
(Figure 4b) but rather at 120° (Figure 4c) and 240°
(Figure 4d). The energetically minimum bisected con-
formers at 0° and 180° were about 3.2 kcal/mol more
stable than the maximum energy conformers at 120° and
240°. The bisected s-cis and trans conformers of i were
fully optimized by a higher level of theory at RB3LYP/
6-31G(d), in which the s-trans conformer is only 0.05 kcal/
mol more stable than the s-cis. When a methyl group was
introduced into the cyclopropane ring at the position cis
to the nitrone moiety of i, namely ii, the energy profile
became asymmetric, as shown in Figure 3b. The energy
was quite high at a 160° angle, due to the steric effect of
the methyl group. The minimum energy values were
observed in an s-trans-like conformer at 20° and also in
an s-cis-like conformer at 200°, while the s-trans-like
conformer was slightly (about 0.8 kcal/mol) more stable
than the s-cis-like. These calculations demonstrate that
only the two energy minimum conformers exist, the s-cis
and s-trans for i and the s-cis-like and s-trans-like for ii,
and that the energy differences between the minimum
energy conformers might be insignificant.
SCHEME 3
These results suggested that the above stereoselective
addition to the nitrone 1 might also occur via a chelation-
controlled pathway (D), as shown in Scheme 3, although
such a 1,5-chelation-controlled addition seemed un-
usual.10,13 Thus, we planned to clarify the actual reaction
pathway of the stereoselective addition to C-cyclopropyl-
aldonitrones.
Results and Discussion
Conformational Analysis by Calculations. Al-
though a number of theoretical and experimental studies
on the conformation of vinylcyclopropanes, cyclopropane-
carbaldehydes, and cyclopropyl ketones have been carried
out,1,6a,c,7,9,12 our previous study11 may be the only one to
investigate the conformation of a C-cyclopropylaldoni-
trone. It would be important to confirm whether the
bisected s-trans and/or s-cis conformations generally
predominate in C-cyclopropylaldonitrones. In particular,
a quantitative study on the conformation would be useful
for discussing and understanding the reaction pathway.
We investigated the conformational stability of C-
cyclopropylaldonitrones by ab initio calculations using
structurally simplified model compounds, i.e., C-cyclo-
propyl-N-methylaldonitrone (i) and C-(cis-2-methylcyclo-
propyl)-N-methylaldonitrone (ii) (Figure 2). The rota-
tional barrier energy around the N1-C1-C2-H2 dihedral
angle on the model compounds was calculated on the
We next investigated the conformation of the two
model compounds in their nitrone O-protonated forms,
i.e., iH and iiH (Figure 2), which could be simplified
models of a Lewis acidic metal ion-coordinated structure.
Interestingly, as shown in Figure 3a,b, the protonation
drastically changed the energy profiles. The energy of the
protonated iH is at a minimum in the bisected s-trans
conformer at 0° (360°) and in the s-cis conformer at 180°
(14) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J. A. Gaussian 98, revision A.6; Gaussian, Inc.: Pittsburgh, PA,
1998.
(12) Kazuta, Y.; Abe, H.; Yamamoto, T.; Matsuda, A.; Shuto, S.
Tetrahedron 2004, 60, 6689-6703.
(13) (a) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556-569. (b)
Huryn, D. M. Comprehensive Organic Synthesis; Schreiber, S. L., Ed.;
Pergamon Press: Oxford, 1991; Vol. 1, pp 49-75. (c) Reetz, M. T. Acc.
Chem. Res. 1993, 26, 462-468. (d) Mengel, A.; Reiser, O. Chem. Rev.
1999, 99, 1191-1223.
J. Org. Chem, Vol. 69, No. 26, 2004 9145

Kazuta et al.
FIGURE 4. Newman projection of the maximum energy
conformers of i (a and b) and its protonated form iH (c and d).
FIGURE 5. Minimum energy s-cis- and s-trans conformers
and their relative energies obtained by the ab initio calcula-
tions of the model compounds in their protonated forms iH
(a) and iiH (b).
FIGURE 3. Rotational barrier energies around the N1-C1-
C2-H2 dihedral angle of the model compounds i and its
protonated form iH (a) and ii and its protonated form iiH (b).
4.93 kcal/mol (Figure 5b), which suggests that the s-trans
is almost the only conformer occurring in the protonated
iiH. These calculations clearly demonstrate that C-
cyclopropylaldonitrones can be significantly stabilized in
the bisected s-trans conformation when a Lewis acidic
metal coordinates to the nitrone oxygen.
Grignard Addition with a Nonchelating Sub-
strate. With the calculation results suggesting that the
s-trans conformer is very stable under the Lewis acidic
conditions in mind, we next examined the Grignard
reaction of a C-cyclopropylaldonitrone 7 (Scheme 4), in
which the carbamoyl group of 1 at the position cis to the
nitrone moiety on the cyclopropane ring was replaced
with a tert-butyldiphenylsilyl (TBDPS) oxymethyl group.
Substrate 7 was designed to determine whether chelation
is important in the Grignard addition to C-cyclopropyl-
aldonitrones, since the nonchelating nature of the silyl
ether oxygen is well-known.13 Treatment of the known
aldehyde 1012 with N-BnNHOH‚HCl formed the desired
nitrone 7 quantitatively (Scheme 5), and the conforma-
tion was investigated by NOE experiments. When the
(Figure 3a) and is at a maximum in the exactly perpen-
dicular conformers at 90° (Figure 4a) and at 270° (Figure
4b). It should be noted that the s-trans conformer is not
only significantly more stable than the perpendicular
conformers (∆E ) 10 kcal/mol), but also, importantly, it
is more stable than the s-cis-conformer (∆E ) 3.5 kcal/
mol). The energy profile of the protonated iiH bearing a
cis-methyl substituent is similar to that of iH (Figure 3b).
However, in iiH, the bisected s-trans conformer is
relatively more stable than that in iH, due probably to
the steric demand of the methyl substituent.
The bisected s-cis and s-trans conformers of iH and iiH
were fully optimized by a higher level theory at RB3LYP/
6-31G(d), and the stable conformations obtained and their
relative energies are shown in Figure 5. The s-trans
conformer was 3.41 kcal/mol more stable than the s-cis
conformer for iH (Figure 5a). The energy difference
between the s-trans and the s-cis conformers for iiH is
9146 J. Org. Chem., Vol. 69, No. 26, 2004

Bisected s-Trans Conformation-Controlled Grignard Addition
SCHEME 4
FIGURE 7. Transition-state model for nucleophilic attack on
the Mg2+-coordinated C-cyclopropylaldonitrone.
have formed a chelate under the reaction conditions.
When MgBr2 was used as an additive in the Grignard
reaction, the anti-product 9 was formed exclusively and
the yield was also improved (entry 2 in Table 2).
SCHEME 5
The stereochemistry of the anti-product 9 was deter-
mined by chemical transformations. We previously re-
ported that the configuration of compounds with a
bicyclo[3.1.0]hexane system, such as the 3-oxabicyclo-
[3.1.0]hexane derivative 14 (Figure 6b), can be deter-
1
mined by the J values in the H NMR.6c Thus, 9 was
converted into the 3-azabicyclo[3.1.0]hexane derivative
13, via reduction of the N-oxide moiety, de-O-silylation,
and PDC oxidation, as shown in Scheme 5. The J2,1′ value
of 13 was about 0 Hz, similar to that of 14, indicating its
1′S-configuration (Figure 6b).
TABLE 2. Addition Reactions of MeMgBr to
C-Cyclopropylaldonitrone 7a
reagent
(equiv)
additive
(equiv)
yield
These results using the nonchelating silyl ether-type
substrate 7 confirmed that the highly anti-selective
Grignard addition reaction on the cis-substituted C-
cyclopropylaldonitrones occurs via the bisected s-trans
conformation-controlled pathway.
Discussion. It has been recognized that the conforma-
tion of the transition state and the intermediate can be
strongly influenced by conformational effects which
stabilize the ground-state conformation.15 In nucleophilic
addition to C-cyclopropylaldonitrones, the conformations
of the transition state and the ground state would be
similar because of the characteristic stereoelectronic
feature of C-cyclopropylaldonitrones.
entry
(8 + 9)b
syn/antic
1
2
MeMgBr (3)
MeMgBr (3)
none
MgBr2 (2)
25 (70)
50 (39)
6:94
only anti
a The reaction was performed in Et2O/THF (2:1) at -78 °C for
8 h. b The substrate 7 was recovered in 70% (entry 1) and 39%
(entry 2) yields. c Determined by 1H NMR.
The Walsh model16 is useful in understanding the
conjugating ability of the cyclopropane ring, by which the
bisected conformational stability is explained through
interaction of the p-orbitals on the cyclopropyl carbons
and the adjacent π* orbital (CdN in the case of C-
cyclopropylaldonitrones) because of their planar arrange-
ment.1a,b,7h Such orbital interaction should also effectively
stabilize the transition state of the nucleophilic attack.
In the course of the attack, the p-orbital of the cyclopro-
pane ring, which can be characterized as a strong
electron-donor,1a interacts with the antibonding orbital
(σ**) of the electron-deficient incipient bond between the
nucleophile and the nitrone carbon. This p-σ** orbital
interaction is maximized in the bisected conformation,
in which the orbitals of the newly forming bond and the
cyclopropane C-C bond are in an almost planar arrange-
ment, as shown in Figure 7. This kind of stabilization of
FIGURE 6. NOE experiments of the C-cyclopropylaldonitrone
7 (a) and coupling constants of the 3-oxa- and 3-azabicyclo-
[3.1.0]hexane derivatives 13 and 14 (b).
1′-H was irradiated, NOEs were observed at the 3-H,
which is in the position cis to the nitrone moiety, of the
cyclopropane ring (2.8%), and at the benzyl methylene
proton (5.4%), and silyloxymethylene protons (2.5%,
0.4%), as shown in Figure 6a. Thus, the compound is a
Z-nitrone restricted in the bisected s-trans-like conforma-
tion in solution.
The reaction of 7 with MeMgBr was first carried out
at -78 °C in Et2O/THF. The reaction conditions were the
same as those previously employed for 1 (entry 1 in Table
1). The reaction of the silyl ether substrate 7 gave highly
stereoselectively the anti-product 9 (syn/anti ) 6:94,
entry 1 in Table 2), despite its nonchelating silyl ether
structure. The syn/anti-ratio in the reaction was higher
than that of the corresponding carbamoyl-type substrate
1 (entry 1 in Table 1, syn/anti ) 10:90), which might
(15) For examples, see: (a) Pothier, N.; Goldstein, S.; Deslong-
champs, P. Helv. Chim Acta 1992, 75, 604-620. (b) Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168-169.
(c) Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123,
11870-11882. (d) Tamura, S.; Abe, H.; Matsuda, A.; Shuto, S. Angew.
Chem., Int. Ed. 2003, 42, 1021-1023.
(16) Walsh, A. D. Nature (London) 1947, 159, 712-713.
J. Org. Chem, Vol. 69, No. 26, 2004 9147

Kazuta et al.
FIGURE 9. Cyclopropanecarbaldehyde (iii) and its proto-
nated form (iiiH).
FIGURE 8. Mg2+-coordinated bisected s-cis and s-trans
conformers of C-cyclopropylaldonitrone (a) and cyclopropan-
ecarbaldehyde (b).
the transition states of nucleophilic attack due to the
orbital interaction of σ** has been explained by Cieplak.17
The ab initio calculations on C-cyclopropyl-N-methyl-
aldonitrone (i) showed that although its energy is at a
minimum in the bisected s-cis and s-trans conformations,
the energy is not at a maximum in their perpendicular
conformations. The maximum energy was observed at the
angle of 120° (Figure 4c) and 240° (Figure 4d), where the
cyclopropane ring and the nitrone CdN bond are almost
eclipsed. The results suggest that the torsional strain
between the cyclopropane ring and the CdN bond may
significantly affect the nitrone conformation. The results
of the calculations on the protonated nitrones as models
of the Mg2+-coordinated reactive intermediates are vitally
important in understanding the reaction pathway of the
Grignard reactions of C-cyclopropylaldonitrones, since,
during the course of the reaction, the coordination of Mg2+
to the oxygen atom makes the nitrone CdN bond reactive
to nucleophiles, which is essential for nucleophilic attack
to occur. The protonation of the oxygen atom lowers the
energy of the π* of the CdN bond, where the p-π*
interaction is able to lower the energy of the bisected
conformers more effectively than that of the unprotonated
nitrone. This was supported by the results of calculations
on i and its protonated form iH, namely that the
rotational energy barrier, i.e., the energy difference
between the energetically minimum bisected conformer
and the maximum conformer, tripled when the nitrone
oxygen was protonated (about 3.2 kcal/mol for the un-
protonated i and more than 10 kcal/mol for the proto-
nated iH). In the protonated form iH the calculated
energy is at a maximum at the exactly perpendicular
conformers (Figure 4a,b), where the p-π* orbital interac-
tion should be at a minimum. These calculations suggest
FIGURE 10. Rotational barrier energies around the O1-C1-
C2-H2 dihedral angle of the model compound iii and its
protonated form iiiH.
Thus, the high stereoselectivity is explained by nucleo-
philic attack on the less hindered side of the CdN bond
of the Mg2+-coordinated bisected s-trans conformation,
which is significantly stabilized by the p-π* orbital
interaction.
A question might arise from the above results, to wit,
why does the Grignard addition to cis-substituted cyclo-
propanecarbaldehydes, which seem to have structural
and stereoelectronic features similar to the corresponding
C-cyclopropylaldonitrones, not proceed stereoselectively
via the bisected transition state pathway?11 For example,
Grignard addition of MeMgBr to the cyclopropanecar-
baldehyde 10 (structure shown in Scheme 5), which bears
the cis-TBDPSOCH2 substituent on the cyclopropane ring
as in the nitrone 7, gave a mixture of the syn/anti-
products almost nonstereoselectively (e.g., at -78 °C in
THF, syn/anti ) 2.8:1; at -78 °C in CH2Cl2, syn/anti )
1.3:1).12
Conformations of cyclopropanecarbaldehyde (iii) and
its formyl O-protonated form iiiH (Figure 9) were ana-
lyzed by ab initio methods similar to those described
above, and the results are shown in Figure 10. The
energy profile of iii shows that the bisected s-cis and the
s-trans-conformers are significantly stabilized compared
with the other conformers, similar to the profile of the
corresponding nitrone i. However, the profile of the
protonated iiiH demonstrates that the s-trans and the
s-cis conformers have almost the same energy, which is
in contrast to the results on the protonated nitrone iH
that when the nitrone oxygen is coordinated with Mg2+
,
the dominant factor determining the conformation of the
molecule is the orbital interaction. Although the bisected
s-cis and s-trans conformers should be similarly stabilized
by the orbital interaction in their coordinated (proto-
nated) form, the calculations proved that the s-trans
conformer is significantly more stable than the s-cis. In
the coordinated bisected s-cis-conformer, steric repulsion
between the O-Mg (O-H in the calculations) moiety and
cyclopropane moiety would occur, as shown in Figure 8a,
resulting in a net stabilization of the s-trans conformer.
(17) (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540-4552. (b)
Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J. Am. Chem. Soc. 1989,
111, 8447-8462. (c) Cieplak, A. S. Chem. Rev. 1999, 99, 1265-1336.
9148 J. Org. Chem., Vol. 69, No. 26, 2004

Bisected s-Trans Conformation-Controlled Grignard Addition
(1 H, d, -CH2OSi, J ) 10.9 Hz), 3.83 (1 H, d, -CH2Ph, J )
13.3 Hz), 3.90 (1 H, d, -CH2OSi, J ) 10.9 Hz), 4.02 (1 H, d,
-CH2Ph, J ) 13.3 Hz), 4.62 (1 H, br s, -OH), 7.22-7.40 (20
H, m, aromatic). 9: 1H NMR (500 MHz, CDCl3) δ 0.87 (1 H,
dd, H-3a, J ) 4.8, 5.6 Hz), 0.95 (9 H, s, -C(CH3)3), 1.07 (1 H,
dd, H-3b, J ) 4.8, 9.2 Hz), 1.28 (3 H, d, Me, J ) 5.4 Hz), 1.44
(1 H, ddd, H-2, J ) 5.6, 9.2, 9.2 Hz), 2.74 (1 H, m, CH-N),
3.86 (1 H, d, -CH2Ph, J ) 13.4 Hz), 3.87 (1 H, d, -CH2OSi, J
) 10.9 Hz), 3.98-4.00 (2 H, m, -CH2OSi and -CH2Ph), 4.95
(1 H, br s, -OH), 7.19-7.50 (20 H, m, aromatic); 13C NMR
(125 MHz, CDCl3) δ 14.8 (C-3), 19.2 (C-2′′), 19.2 (-C(CH3)3),
26.8 (-C(CH3)3), 28.8 (C-1), 33.1 (C-2), 61.1 (C-1′′), 62.4 (C-
1′), 68.00 (-CH2Ph), 126.3, 127.0, 127.5, 127.6, 128.0, 128.3,
129.3, 129.5, 129.5, 129.7, 133.3, 133.5, 135.6, 135.7, 138.7,
144.7; HR-MS (FAB) calcd C35H42NO2Si 536.2985, found
536.2961 ((M + H)+).
(1S,2R)-2-[(S)-1-(Benzylamino)ethyl]-1-tert-butyldiphen-
ylsilyloxymethyl-1-phenylcyclopropane (11). A mixture
of 9 (27 mg, 50 µmol) and Zn powder (33 mg, 0.50 mmol) in
AcOH/CH2Cl2 (1:5, 1.2 mL) was stirred at room temperature
for 3 h. The mixture was filtered through a Celite pad, and
the filtrate was evaporated. The residue was purified by
column chromatography (silica gel; AcOEt/hexane 1:1, CHCl3/
AcOEt 1:1, then MeOH/CHCl3 1:10) to give 11 (20 mg, 77%)
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.47 (1 H, dd,
J ) 4.8, 6.0 Hz), 0.86 (9 H, s), 0.91 (1 H, dd, J ) 4.8, 8.8 Hz),
1.22 (3 H, d, J ) 6.2 Hz), 1.43 (1 H, ddd, J ) 6.0, 8.8, 8.8 Hz),
2.22 (1 H, br s), 2.51 (1 H, dq, J ) 6.0, 8.8 Hz), 3.65 (1 H, d, J
) 11.0 Hz), 3.81 (1 H, d, J ) 13.6 Hz), 3.96 (1 H, d, J ) 13.6
Hz), 3.99 (1 H, d, J ) 11.0 Hz), 7.04-7.06 (2 H, m), 7.12-7.16
(5 H, m), 7.23-7.43 (11 H, m), 7.49-7.51 (2 H, m); 13C NMR
(125 MHz, CDCl3) δ 14.7, 19.0, 19.6, 26.8, 31.9, 33.4, 51.0, 53.3,
68.1, 126.5, 126.6, 127.4, 127.7, 128.0, 128.1, 128.27, 129.3,
129.5, 130.7, 132.8, 133.8, 135.5, 135.7, 144.5; HR-MS (FAB)
calcd C35H42NOSi 520.3036, found 520.3041 ((M + H)+).
(1S,2R)-2-[(S)-1-(Benzylamino)ethyl]-1-hydroxymethyl-
1-phenylcyclopropane (12). A mixture of 11 (10 mg, 20
µmol) and TBAF (1.0 M in THF, 40 µL, 40 µmol) in THF (1
mL) was stirred at room temperature for 12 h. The mixture
was evaporated, and the residue was partitioned between
CHCl3 and H2O. The organic layer was washed with brine,
dried (Na2SO4), evaporated, and purified by column chroma-
tography (silica gel; CHCl3/AcOEt 1:1 then, MeOH/CHCl3 1:10)
to give 12 (5.6 mg, 100%) as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 0.76 (1 H, dd, J ) 4.7, 5.4 Hz), 1.17 (1 H, dd, J ) 4.7,
8.6 Hz), 1.27 (1 H, ddd, J ) 5.4, 8.6, 8.6 Hz), 1.42 (3 H, d, J )
6.2 Hz), 2.65 (1 H, dq, J ) 6.2, 8.6 Hz), 3.55 (1 H, d, J ) 12.2
Hz), 3.73 (1 H, d, J ) 12.2 Hz), 3.98 (1 H, d, J ) 12.2 Hz), 4.18
(1 H, d, J ) 12.2 Hz), 7.16-7.38 (10 H, m); 13C NMR (125 MHz,
CDCl3) δ 19.2, 19.5, 32.3, 32.8, 50.0, 54.5, 68.5, 126.1, 127.4,
128.1, 128.2, 128.6, 128.7, 138.7, 144.7; HR-MS (FAB) calcd
C19H24NO 282.1858, found 282.1871 ((M + H)+).
(1S,4S,5R)-4-Methyl-2-oxo-1-phenyl-3-benzyl-3-aza-
bicyclo[3.1.0]hexane (13). A mixture of 12 (5.6 mg, 20 µmol)
and PDC (15 mg, 40 µmol) in CH2Cl2 (3 mL) was stirred at
room temperature for 12 h. The resulting mixture was filtered
through a pad of Florisil and celite, and the filtrate was
evaporated. The residue was purified by column chromatog-
raphy (silica gel; AcOEt/hexane 1:4) to give 13 (5.2 mg, 94%)
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.95 (1 H, dd,
H-6a, J6a,6b ) 4.4, J6a,5 ) 4.8 Hz), 1.31 (3 H, d, 4-Me, J ) 6.4
Hz), 1.43 (1 H, dd, H-6b, J6b,6a ) 4.4, J6b,5 ) 7.6 Hz), 1.84 (1 H,
dd, H-5, J5,6a ) 4.8, J5,6b ) 7.6 Hz), 3.40 (1 H, q, H-4, J ) 6.4
Hz), 3.95 (1 H, d, -CH2Ph, J ) 14.9 Hz), 4.95 (1 H, d, -CH2-
Ph, J ) 14.9 Hz), 7.21-7.45 (10 H, m, aromatic); 13C NMR
(125 MHz, CDCl3) δ 19.0, 20.7, 26.7, 33.8, 44.1, 53.2, 127.1,
127.5, 128.2, 128.4, 128.6, 128.7, 136.5, 137.4, 173.7; HR-MS
(FAB) calcd C19H20NO 278.1545, found 278.1530 ((M + H)+).
which show that the s-trans conformer is considerably
more stable than the s-cis conformer (Figure 3a). As
shown in Figure 8b, steric repulsion in both the s-cis and
the s-trans conformers of the aldehyde is inconsequential;
therefore, these conformers would have almost the same
stability. Accordingly, the Grignard additions to the cis-
substituted cyclopropanecarbaldehydes are likely to pro-
ceed via both the bisected s-cis and the s-trans reaction
pathways to result in an almost nonstereoselective
outcome.
Conclusion. Theoretical calculations of C-cyclopropyl-
aldonitrones clarified that the coordination of Mg2+ at
the nitrone oxygen significantly stabilizes the bisected
s-trans conformer due to the effective hyperconjugation
between the π* of the nitrone CdN bond and the electron-
donating cyclopropane orbitals. In nucleophilic addition
to C-cyclopropylaldonitrones, the bisected transition state
can be stabilized by a similar orbital interaction between
the p-orbital of the cyclopropane ring and the antibonding
orbital of the electron-deficient incipient bond. Thus, a
highly stereoselective Grignard addition was realized by
nucleophilic attack on the less hindered side of the CdN
bond of the substrates in the Mg2+-coordinated bisected
s-trans conformation.
Experimental Section
(Z)-N-[(1S,2R)-2-tert-Butyldiphenylsilyloxymethyl-2-
phenylcyclopropylmethylene]benzylamine N-Oxide (7).
A mixture of 1012 (415 mg, 1.00 mmol) and N-benzylhydroxyl-
amine hydrochloride (192 mg, 1.20 mmol) in CH2Cl2 (5 mL)
was stirred at room temperature for 2 h. The resulting mixture
was concentrated in vacuo (for removing CH2Cl2), and the
residue was partitioned between AcOEt and H2O. The organic
layer was washed with brine, dried (Na2SO4), evaporated, and
purified by column chromatography (silica gel; AcOEt/hexane
1:1, then MeOH/CHCl3 1:49) to give 7 as white crystals (519
mg, 100%): mp (hexane-AcOEt) 99-100 °C; [R]23D +71.39 (c
1.190, CHCl3); 1H NMR (500 MHz, CD2Cl2) δ 0.99 (9 H, s,
-C(CH3)3), 1.27 (1 H, dd, H-3a, J ) 4.8, 5.4 Hz), 1.44 (1 H, dd,
H-3b, J ) 4.8, 8.9 Hz), 2.63 (1 H, ddd, H-2, J ) 5.4, 7.7, 8.9
Hz), 3.69 (1 H, d, -CH2OSi, J ) 11.0 Hz), 3.91 (1 H, d, -CH2-
OSi, J ) 11.0 Hz), 4.86 (1 H, d, -CH2Ph, J ) 13.4 Hz), 4.82 (1
H, d, -CH2Ph, J ) 13.4 Hz), 6.71 (1 H, d, H-1′ (CHdN), J )
7.7 Hz), 7.21-7.51 (20 H, m, aromatic); NOE (400 MHz, CD2-
Cl2, 24 °C) 2.8 (H-1′ f H-3a), 2.5 (H-1′ f -CH2OSi), 0.9 (H-1′
f -CH2OSi), 5.4 (H-1′ f -CH2Ph); 13C NMR (125 MHz, CD2-
Cl2) δ 17.8 (C-3), 19.3 (-C(CH3)3), 21.7 (C-2), 26.9 (-C(CH3)3),
36.9 (C-1), 68.0 (C-1′), 69.4 (-CH2Ph), 126.3, 127.94, 128.0,
128.5, 128.9, 129.0, 129.4, 129.9, 130.0, 130.2, 133.4, 133.4,
134.0, 135.8, 135.8, 137.43, 142.77; LR-MS (FAB) m/z 520 ((M
+ H)+, 100). Anal. Calcd for C34H37NO2Si: C, 78.57; H, 7.18;
N, 2.69. Found: C, 78.33; H, 7.24; N, 2.88.
General Procedure for the Addition of Grignard
Reagent to Nitrone 7. A mixture of nitrone 7 (52 mg, 0.10
mmol) and MgBr2 (37 mg, 0.20 mmol) in a solvent (3 mL) was
stirred at room temperature for 30 min and then cooled to -78
°C. To the mixture was added a solution of MeMgBr [0.14 mL,
0.20 mmol, 1.4 M in toluene/THF (3:1)], and the resulting
mixture was stirred for 8 h at the same temperature. After
addition of sarturated aqueous NH4Cl, the mixture was
evaporated, and the residue was partitioned between AcOEt
and H2O. The organic layer was washed with brine, dried (Na2-
SO4), evaporated, and purified by column chromatography
(silica gel; AcOEt/hexane 1:4) to give a mixture of 8 and 9 or
pure 9. The mixture of 8 and 9: 1H NMR (500 MHz, CDCl3)
for 8 δ 0.85 (1 H, dd, H-3a, J ) 4.7, 5.5 Hz), 0.95 (9 H, s,
-C(CH3)3), 1.09 (1 H, dd, H-3b, J ) 4.7, 8.6 Hz), 1.44 (1 H, m,
H-2), 1.60 (3 H, d, Me, J ) 6.4 Hz), 2.75 (1 H, m, CH-N), 3.64
Calculations. All ab initio and DFT calculations were
performed using the Gaussian 98 program14 on an SGI O2
workstation. The N1(O1)-C1-C2-H2 dihedral angle of the
compounds was rotated from 0° to 360° at the intervals of 20°,
J. Org. Chem, Vol. 69, No. 26, 2004 9149

Kazuta et al.
and the conformations were optimized at RHF/3-21G(d).
Finally, single-point energies were calculated at RB3LYP/6-
31G(d) (Figures 3 and 10). The bisected s-cis and s-trans
conformers were fully optimized at RB3LYP/6-31G(d), and
their single point energies were calculated by RB3LYP/6-31G-
(d) (Figure 5).
A. Maeda, and S. Oka (Center for Instrumental Analy-
sis, Hokkaido University) for technical assistance with
NMR, MS, and elemental analyses and to Daiso Co.,
Ltd., for the gift of chiral epichlorohydrins.
Supporting Information Available: General experimen-
tal methods, 1H NMR charts of 9, 11, 12, and 13, absolute
energies, and atomic coordination of the calculated structures
for the model compounds i, ii, and iii and their protonated
forms iH, iiH, and iiiH. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) (A.M.), a Grant-in-Aid for Scientific
Research (S.S.), and Research Fellowships for Young
Scientists (H.A.) from the Japan Society for the Promo-
tion of Science. We are grateful to Ms. H. Matsumoto,
JO048637E
9150 J. Org. Chem., Vol. 69, No. 26, 2004